Phase 5e mutant-ensemble re-dock LAUNCHED: 11 ligands (LEGACY_LEADS + V2_HITS + tafamidis-analog) × 20 Phase 5d mutant snapshots × Vina exh=16, box centre per-snapshot from K1141+ring Cα centroid, 18 Å box. Gates v3b YELLOW-on-mutant validity. ~15 min wall. A held, next_step updated.
2026-04-23
Phase 4h Tafamidis-Playbook Library drafted: 30-compound prioritized target list, 5 cores × 6 polar distal subs × 2 acid bioisosteres = 60 combinatorial pruned to top 30. Tier 1 commercial + Tier 2 2-step in-house = 8 compounds orderable this week (tafamidis #5, iododiflunisal 12, benzoxazole-3CN #1, benzoxazole-3OMe #2). 3 Phase 6b covalent warheads (salicylaldehyde imine, α-cyanoacrylate Michael, acyl-hydrazone). Predicted ΔG improvement -0.5 to -2.0 kcal/mol over parent niflumic −6.18. 6-target cochlear channel off-target panel pre-scored (TRPM4/Cx50/BK/KCNQ4/TMEM16A/COX) queued as Phase 6c 30×6 = 180 docks, ~1 h local wall. A held. No empirical data yet; this seeds Phase 3c v4 virtual screen + Phase 8 wet-lab synthesis Stage 1. → STRC h01 Phase 4h Tafamidis Playbook Library 2026-04-23
Phase 5d E1659A MD LAUNCHED (PID 28875 nohup, 19:34 local 2026-04-23, ETA ~23:00 local = 3.5 h wall): full-length AF3 mutant job3-mutant.cif chain A (1775 residues), verified K1141=LYS + E1659=ALA pre-run. 645,244-atom system (4× Phase 5a) solvated with TIP3P + 0.15 M NaCl, AMBER14SB, 2 ns production × 20 snapshots. SMOKE (50 ps × 2) passed at 13.86 ns/day. Closes critical gap: all prior Phase 5a/5b/5c were on WT Ultra-Mini (594-1294 full-length) which excludes E1659. Phase 5d is the first MD on the actual disease target. Phase 5e script written (mutant-ensemble Vina re-dock of LEGACY_LEADS + V2_HITS + tafamidis-analog, pocket box centre derived per-snapshot from K1141 + ring residue Cα centroid, 18×18×18 Å box, cpu=8 parallel). Phase 5e scheduled post-Phase 5d delivery + post-v3b Stage 2 (CPU schedule). Verdict deferred. → STRC h01 Phase 5d E1659A MD 2026-04-23 expected
Fenamic Scaffold Tox Audit: A held, scaffold-developability risk sharpened. Parent fenamates (niflumic / flufenamic / meclofenamic / mefenamic / tolfenamic) NOT developable as-is for pediatric cochlear target — ion-channel promiscuity (TRPM4 2.8 µM, Cx50 3 µM gap junctions, BK 25 µM, KCNQ-family, TMEM16A 12 µM) overlaps Kd ~30 µM window; mefenamic seizure risk ≥2.5 g; COX inhibition reduces cochlear blood flow (therapeutically antagonistic). Scaffold developable via tafamidis-style optimization (benzoxazole bioisostere + polar distal ring subs); direct precedent flufenamic → tafamidis → FDA 2019. Phase 4h: parents as MD PROBES only, not wet-lab triage candidates. → STRC h01 Fenamic Scaffold Tox Audit 2026-04-23
Phase 3c v3b + 6b LAUNCHED (in progress, PID 73601 nohup detached, ETA ~5.7h): fenamic-focused 12,253-ligand library (619-lig combinatorial → expanded to 12k via 8 cores × 57 N-aryl subs × 5 acid bioisosteres × 8 ring subs + 6 covalent warheads on 8 cores × 10 hot N-aryls × 2 acid bioisosteres). Two-stage ensemble dock identical to Phase 3c v2b: Stage 1 on snap_008 exh 8 × 3 modes (0.65 lig/s, ETA 313 min), Stage 2 on top-50 × 5 k-means-selected conformers exh 16 × 5 modes. Checkpoint JSON every 100 lig. Expected delivery ~04:30 local. Output → pharmacochaperone_phase3c_v3b_ensemble_dock.json. Will produce proof note STRC h01 Phase 3c v3b Fenamic + Covalent Screen 2026-04-23 on completion. → STRC h01 Phase 3c v2 Expanded Screen 2026-04-23 (precedent)
Phase 3c v2 expanded virtual screen: RED overall, partial progress. 667-ligand library (619 RDKit combinatorial scaffold × acid bioisostere + 29 curated FDA/literature drugs) × 2-stage ensemble docking (Stage 1 snap_008 exh 8 on all 667 → 8.5 min; Stage 2 top-30 × 5 k-means conformers exh 16 → 4 min, total 13 min wall). Top hits niflumic-acid / flufenamic-acid / sulfasalazine at Kd ≈ 30 μM, f_PC ≈ 0.125 at [L]=10 μM — 1.7× better Kd than Phase 5b diflunisal baseline. Fenamic-acid family (2-arylaminobenzoic) = new scaffold direction; tetrazole bioisostere competitive with COOH. 0 GREEN / 0 YELLOW / 30 RED. Ceiling analysis: to cross f_PC ≥ 0.30 (MILD-MODERATE) need ΔG ≈ -7.06 kcal/mol (0.88 below current best). A held, all scores unchanged. Next-step reordered: (1) Phase 3c v3 ZINC22 bioactives ~20k library, (2) Phase 3c v4 fragment-growing niflumic core, (3) Phase 6b reversible covalent Lys warhead. → STRC h01 Phase 3c v2 Expanded Screen 2026-04-23
Phase 5c cryptic pocket analysis: K1141 site GREEN-LIGHT. Custom grid-cavity + Kabsch-aligned RMSF analysis on Phase 5a 20-snapshot trajectory (fpocket 4.0 brew build broken on qhull). K1141 pocket Cα RMSF 0.62 Å vs global 1.23 Å (2× more rigid than average); local void volume 719-850 ų across 20 frames (~15% CV, pocket does not collapse or shift geometry). Global cavity scan (snap_010, 26-direction burial ≥16/26): no alt cavity > 152 ų, nearest at 18.7 Å (91 ų). Phase 5b RED-LIGHT confirmed chemistry-limited not site-limited. Phase 3c v2 expanded screen targeted at K1141 with ensemble receptor docking (use all 20 Phase 5a snapshots) validated as next move. A held, all scores unchanged. → STRC h01 Phase 5c Cryptic Pocket Analysis 2026-04-23
Phase 5a MD pipeline validated on local Mac: 62 ns/day OpenMM OpenCL (Metal backend) on 164 k-atom solvated Ultra-Mini × TMEM145 chain A. 2 ns production delivered 20 snapshots, 45 min wall time. Replaces deferred GROMACS/AmberTools scaffold which required A100 rental. Phase 5b Vina ensemble re-docking of Phase 4b top-5 leads + diflunisal positive control against 20 snapshots → all f_PC at [L]=10 μM < 0.10 (best = diflunisal positive 0.083, best lead = naphthalene-2-COOH 0.047). Phase 4b single-structure was over-optimistic by +0.36 to +0.92 kcal/mol. RED-LIGHT: current shortlist insufficient for NORMAL-rescue monotherapy. A held, scores unchanged (mechanism intact, Misha fit intact; only shortlist insufficient). Next step: Phase 3c v2 expanded virtual screen (DrugBank FDA + ZINC22 carboxylate tranche + fragment-based; ensemble filter ΔG ≤ −7.5 kcal/mol). → STRC h01 Phase 5 MD Ensemble Rescoring 2026-04-23
Misha compound-het stack integration: A held, scores unchanged, framing strengthened. Per Misha Compound-Het Therapy Stack Model binary-functional-OHC model, h01 PC is the only monotherapy route to NORMAL (≤25 dB ABR) for Misha — because PC reaches every OHC (including non-transduced ones where h03 AAV by definition does nothing), rescuing maternal E1659A to 0.5 × f_mat_treated ≥ θ. Required f_PC ≥ 0.50 (mild E1659A) to ≥ 0.75 (severe). Phase 5 MD ensemble MM-GBSA priority strengthened — f_PC is the critical-path deliverable. → Misha Compound-Het Therapy Stack Model
Post-audit housekeeping: A held. TPSA docstring in phase3b_virtual_screen.py corrected (descriptor-only, not composite scoring; CNS TPSA bracket removed — STRC extracellular). Druggability cross-phase incomparability flagged in Phase 1/2/2b. No fabricated ranges added. → STRC h01 Parameter Provenance Audit 2026-04-23